Many CNS disorders, such as HIV-1-associated neurocognitive disorders (HAND), involve an inflammatory response that is orchestrated by cells of the innate immune system, namely macrophages and microglia (MG). Hence, there is considerable interest in anti-inflammatory strategies that target these cells. It is known that MG express voltage-gated K+ channel Kv1.3 which is important for MG functionality, but there is very limited information available on how the Kv1.3 channels can be "best" utilized for optimal therapeutic benefit. To this end, we seek funds to study the role of Kv1.3 in HIV-1-associated MG activation, migration, resultant neurotoxin production and consequent neuronal injury as well as the link of Kv1.3 activation to the pathogenesis of neurodegenerative disorders including HAND. Electrophysiological, pharmacological, molecular and immunocytochemical techniques plus CT/SPECT bioimaging will examine the role of Kv1.3 in regulating MG functionality in laboratory and animal models of human disease. First, we will study the role Kv1.3 channels may play in HIVgp120- and HIV/VSV-associated MG activation, migration and resultant production of neurotoxins and consequent neuronal injury. Second, we will investigate intracellular signaling pathways underlying HIVgp120- and HIV/VSV-induced enhancement of Kv1.3 current, activation of MG and resultant neurotoxic activity. Third, we will assess the role of Kv1.3 in a murine model of HIV encephalitis (HIVE) including MG activation, migration and resultant neuronal dysfunction and cognitive decline. Overall, these studies are focused toward not only understanding the role that the Kv1.3 might play in HAND, but also on identifying specific target(s) for development of therapeutic strategies. If successful, these studies will provide a proper roadmap for expected efficacy of Kv channel antagonists in ameliorating brain injury.